Provigil (Modafinil) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Modafinil has been evaluated for safety in over 3500 patients, of whom more than 2000 patients with excessive sleepiness associated with primary disorders of sleep and wakefulness were given at least one dose of modafinil. In clinical trials, modafinil has been found to be generally well tolerated and most adverse experiences were mild to moderate.

The most commonly observed adverse events (>/=5%) associated with the use of PROVIGIL more frequently than placebo-treated patients in the placebo-controlled clinical studies in primary disorders of sleep and wakefulness were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse event profile was similar across these studies.

In the placebo-controlled clinical trials, 74 of the 934 patients (8%) who received PROVIGIL discontinued due to an adverse experience compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for PROVIGIL than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain and nervousness (each <1%). In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses).

Incidence in Controlled Trials

The following table (Table 3) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in patients treated with PROVIGIL than in placebo patients in the principal, placebo-controlled clinical trials.

The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied.

Dose Dependency of Adverse Events

In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of PROVIGIL and placebo, the only adverse events that were clearly dose related were headache and anxiety.

Vital Sign Changes

While there was no consistent change in mean values of heart rate or systolic and diastolic blood pressure, the requirement for antihypertensive medication was slightly greater in patients on PROVIGIL compared to placebo (See PRECAUTIONS).

Weight Changes

There were no clinically significant differences in body weight change in patients treated with PROVIGIL compared to placebo-treated patients in the placebo-controlled clinical trials.

Laboratory Changes

Clinical chemistry, hematology, and urinalysis parameters were monitored in Phase 1, 2, and 3 studies. In these studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of PROVIGIL, but not placebo. Few subjects, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with PROVIGIL in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin.

ECG Changes

No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials following administration of PROVIGIL.

POSTMARKETING REPORTS

In addition to the adverse events observed during clinical trials, the following adverse events have been identified during post-approval use of PROVIGIL in clinical practice. Because these adverse events are reported voluntarily from a population of uncertain size, reliable estimates of their frequency cannot be made.

Hematologic: agranulocytosis

Central Nervous System: symptoms of psychosis, symptoms of mania

Hypersensitivity: urticaria (hives), angioedema

DRUG ABUSE AND DEPENDENCE

CONTROLLED SUBSTANCE CLASS

Modafinil (PROVIGIL) is listed in Schedule IV of the Controlled Substances Act.

ABUSE POTENTIAL AND DEPENDENCE

In addition to its wakefulness-promoting effect and increased locomotor activity in animals, in humans, PROVIGIL produces psychoactive and euphoric effects, alterations in mood, perception, thinking and feelings typical of other CNS stimulants. In in vitro binding studies, modafinil binds to the dopamine reuptake site and causes an increase in extracellular dopamine, but no increase in dopamine release. Modafinil is reinforcing, as evidenced by its self-administration in monkeys previously trained to self-administer cocaine. In some studies, modafinil was also partially discriminated as stimulant-like. Physicians should follow patients closely, especially those with a history of drug and/or stimulant (e.g., methylphenidate, amphetamine, or cocaine) abuse. Patients should be observed for signs of misuse or abuse (e.g., incrementation of doses or drug-seeking behavior).

The abuse potential of modafinil (200, 400, and 800 mg) was assessed relative to methylphenidate (45 and 90 mg) in an inpatient study in individuals experienced with drugs of abuse. Results from this clinical study demonstrated that modafinil produced psychoactive and euphoric effects and feelings consistent with other scheduled CNS stimulants (methylphenidate).

Withdrawal

The effects of modafinil withdrawal were monitored following 9 weeks of modafinil use in one US Phase 3 controlled clinical trial. No specific symptoms of withdrawal were observed during 14 days of observation, although sleepiness returned in narcoleptic patients.